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EP1521748A1 - Nouveaux derives d'anthracene et leur utilisation comme medicaments - Google Patents

Nouveaux derives d'anthracene et leur utilisation comme medicaments

Info

Publication number
EP1521748A1
EP1521748A1 EP03763626A EP03763626A EP1521748A1 EP 1521748 A1 EP1521748 A1 EP 1521748A1 EP 03763626 A EP03763626 A EP 03763626A EP 03763626 A EP03763626 A EP 03763626A EP 1521748 A1 EP1521748 A1 EP 1521748A1
Authority
EP
European Patent Office
Prior art keywords
branched
straight
chain
alkyl
alkoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03763626A
Other languages
German (de)
English (en)
Inventor
Peter Emig
Eckhard Günther
Beate Aue
Emmanuel Polymeropoulos
Silke Baasner
Peter Schmidt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aeterna Zentaris GmbH
Original Assignee
Zentaris AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zentaris AG filed Critical Zentaris AG
Publication of EP1521748A1 publication Critical patent/EP1521748A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/53—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3

Definitions

  • tumors are a fundamental disease of higher organisms in the plant, animal and human kingdoms.
  • the generally recognized multi-step model of cancer development assumes that the accumulation of several mutations in a single cell changes their proliferation and differentiation behavior in such a way that a malignant state with metastasis is ultimately achieved via benign intermediates.
  • the term cancer or tumor hides a clinical picture with more than 200 different individual diseases. Tumor diseases can be benign or malignant.
  • the main tumors are those of the lungs, breast, stomach, cervix, prostate, head and neck, colon and rectum, liver and blood system.
  • the present invention relates to new aryl- and heteroaryl-substituted piperazinylcarbonyl aromatics, their production and use as medicaments, in particular for the treatment of benign and malignant tumors in humans and mammals.
  • Aryl- and heteroaryl-substituted piperazinylcarbonyl derivatives are widely used as pharmacologically active compounds and as synthesis components in pharmaceutical chemistry.
  • the application WO 200059930 describes 2-alkyl-1- (1H-imidazol-1-yl) -4- (1-naphthalenecarbonyl) piperazines which are used in the treatment of prostate carcinomas.
  • the application WO 9714685 derivatives from the 1- (pyrimidinyl) -4- (naphthylcarbonyl) piperazine series are mentioned which are used as lipid peroxidation inhibitors.
  • DL Romero et al. Upjohn Laboratories
  • R, Ri, R 2, R 3 can optionally be bound to the aromatic carbon atoms d to C 10 of anthracene, are the same or different and are independent of one another: hydrogen, straight-chain or branched (CrC 8 ) -alkyl, (C 3 -
  • C 7 -cycloalkyl, straight-chain or branched (C C ⁇ J-alkylcarbonyl, preferably acetyl, hydroxy, straight-chain or branched (CrC 8 ) -alkoxy, preferably methoxy and ethoxy, halogen, straight-chain or branched aryl- (C r C 8 ) -alkoxy , preferably benzyloxy or phenylethyloxy, trityloxy,
  • Alkoxycarbonylamino straight-chain or branched (CC 8 ) - alkylcarbonylamino, preferably acetamino, sulfonyloxy, sulfenyloxy,
  • Alkylcarbonylamino preferably acetamino, sulfonyloxy, sulfenyloxy, sulfinyloxo, nitro, nitroso, thio, straight-chain or branched (C 1 -C 8 ) -alkylthio, cyano, isocyano, straight-chain or branched (dC 8 ) -alkoxycarbonyl, substituted by one or more halogen atoms, straight-chain or branched (CrC 4 ) -alkyl, preferably trifluoromethyl, (C 2 -
  • C 6 ) alkenyl preferably allyl, (C 2 -C 6 ) alkynyl, preferably ethynyl or propargyl, may be substituted,
  • Z is oxygen or sulfur, the radical substituted on the anthracene aromatic
  • n, m independently of one another represent an integer between 0 and 4;
  • R is a straight-chain or branched (d-Ci 2 ) -alkyl radical which can be saturated or unsaturated with one to three double and / or triple bonds and which is unsubstituted or optionally on the same or different C atoms with one, two or several aryl, heteroaryl, halogen, cyano, (-CC 6 ) alkoxycarbonylamino, (dC 6 ) alkoxy, amino, mono-
  • (-C-C 4 ) alkylamino or di- (-C-C 4 ) alkylamino may be substituted; a (C 6 -C 14 ) aryl radical, (C 6 -C 14 ) aryl (C 1 -C 4 ) alkyl radical or one or more heteroatoms selected from the group containing N, O and S ( C 2 -C ⁇ 0 ) heteroaryl or (C 2 -C 10 ) heteroaryl (d -C) alkyl radical, where the (Ci -C 4 ) alkyl radical is unsubstituted or one or more times the same or can be substituted differently with (Ci-C 6 ) alkyl or halogen and the (C 6 -C 1 ) aryl or (C 2 -C 10 ) heteroaryl radical is unsubstituted or one or more times the same or different with straight-chain or branched (d-C 8 ) -alkyl, (C 3 -C 7
  • Alkoxycarbonyl- (dC 6 ) alkyl, (C 2 -C 6 ) alkenyl, preferably allyl, (C 2 -C 6 ) alkynyl, preferably ethynyl or propargyl, may be substituted.
  • the compounds of general structure 1 according to the invention have at least one asymmetry center, they can be in the form of their racemates, in the form of the pure ones
  • Enantiomers and / or diastereomers or in the form of mixtures of these enantiomers and / or diastereomers are present.
  • the mixtures can be present in any mixing ratio of the stereoisomers.
  • the compounds of the invention may be in the form of the tautomers.
  • the compounds of general formula 1 according to the invention which have one or more centers of chirality and which occur as racemates can be separated into their optical isomers, ie enantiomers or diastereomers, by methods known per se.
  • the separation can be carried out by column separation on chiral phases or by recrystallization from an optically active solvent or using an optically active acid or base or by derivatization with an optically active reagent, such as, for example, an optically active alcohol, and subsequent elimination of the rest.
  • the compounds of general formula 1 according to the invention if they have a sufficiently basic group, such as a secondary or tertiary amine, can be converted into salts with inorganic and organic acids.
  • the pharmaceutically acceptable salts of the compounds according to the invention are preferably of the general structure 1 with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, malonic acid, maleic acid, succinic acid, tartaric acid, malic acid, malic acid , Embonic acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid.
  • the salts formed include hydrochlorides, hydrobromides, sulfates, phosphates, methanesulfonates, sulfoacetic acid, tosylates, carbonates, bicarbonates, formates, acetates, triflates, oxalates, malonates, maleates, succinates, tartrates, malates, embonates, mandelates, fu arates, lactates, citrates and glutamines.
  • the stoichiomethes of the salts formed of the compounds according to the invention can be integer or non-integer multiples of one.
  • the compounds of general formula 1 according to the invention if they contain a sufficiently acidic group, such as the carboxy group, can be converted into their physiologically tolerable salts with inorganic and organic bases.
  • inorganic bases are sodium hydroxide, potassium hydroxide, calcium hydroxide, and organic bases are ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dibenzylethylene diamine and lysine.
  • the stoichiometry of the Salts formed of the compounds according to the invention can be integer or non-integer multiples of one.
  • Solvates and in particular hydrates of the compounds according to the invention which, for. B. can be obtained by crystallization from a solvent or from aqueous solution.
  • One, two, three or any number of solvate or water molecules can combine with the compounds according to the invention to form solvates and hydrates.
  • anthracene derivatives are provided according to the general formula 1, in which R, R 1 f R 2 , R 3 , Z, n and m have the meanings given above and
  • R 4 is a phenyl radical or a naphthyl radical, each unsubstituted or one or more times identical or different with straight-chain or branched (dC 8 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, straight-chain or branched (dC 8 ) -Alkylcarbonyl, preferably acetyl, hydroxy, straight-chain or branched (dC 8 ) alkoxy, preferably methoxy and ethoxy, halogen, straight-chain or branched aryl- (dC 8 ) alkoxy, preferably benzyloxy or phenylethyloxy, trityloxy, trimethylsilyloxy, amino, mono - (CrC) -alkylamino, di- (dC) -alkylamino, (C 2 - C 5 ) cycloalkylamino, morpholino, heterocyclyl- (CC 6
  • a 2-, 3-, 5, - or 6-pyrazinyl radical or 2-, 3-, 5, - or 6-pyrazinyl- (C 1 -C 4 ) -alkyl radical where the (d -C 4 ) alkyl radical may be unsubstituted or substituted one or more times identically or differently with (C 1 -C 6 ) -alkyl, halogen and the 2-, 3-, 5, - or 6-pyrazinyl radical may be unsubstituted or one to three times the same or different with hydrogen, straight-chain or branched (dC 8 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, straight-chain or branched (CC 8 ) -alkylcarbonyl, preferably acetyl, hydroxy, straight-chain or branched (dC 8 ) -alkoxy , preferably methoxy and ethoxy, halogen, straight-chain or branched aryl- (dC
  • a 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl residue or 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl- (Ci -C) alkyl radical, halogen may be substituted wherein the (Ci -C) alkyl radical can be unsubstituted or mono- polysubstituted by identical or different (Ci-C6) -alkyl and the 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl residue unsubstituted or mono- to quintuple identical or different with hydrogen, straight-chain or branched (CC 8 ) alkyl, (C 3 -C 7 ) cycloalky, straight-chain or branched (dC 8 ) alkylcarbonyl , preferably acetyl, hydroxy, straight-chain or branched (CC 8 ) alkoxy, preferably
  • (-CC 8 ) -alkylcarbonylamino preferably acetamino, sulfonyloxy, sulfenyloxy, sulfinyloxo, nitro, nitroso, thio, straight-chain or branched (dC 8 ) -alkylthio, straight-chain or branched (dC 8 ) -alkylsulfo, straight-chain or branched (CC 8 ) -alkylsulfoxy, cyano, isocyano, straight-chain or branched cyano- (CC 6 ) -alkyl, preferably cyanomethyl, straight-chain or branched (dC 8 ) -
  • (dC 8 ) -alkoxy preferably benzyloxy or phenylethyloxy, trityloxy, trimethylsilyloxy, amino, mono- (CC 4 ) -alkylamino, di- (-C-C 4 ) -alkylamino, (C 2 - C) cycloalkylamino, morpholino, heterocyclyl- (CC 6 ) -alkoxy, carboxy, imidocarboxy, carboxamidine, straight-chain or branched (CC 8 ) -alkoxycarbonylamino, straight-chain or branched (dC 8 ) -alkylcarbonylamino, preferably acetamoxoxy, sulfooxy, sulfooxy, sulfonyloxy, sulfonyl sulfoxy Nitro, nitroso, thio, straight-chain or branched (dC 8 ) -alkylthio, straight-
  • (d -C 4 ) alkyl radical where the (Ci -C) alkyl radical may be unsubstituted or mono- or polysubstituted in the same or different way with (Ci -C ⁇ ) alkyl or halogen and the or 2-, 3rd -, 5-, 6-, 7-, or 8-quinoxalinyl residue one to five times the same or different with hydrogen, straight-chain or branched (dC 8 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, straight-chain or branched (DC 8 ) -alkylcarbonyl, preferably acetyl, hydroxy, straight-chain or branched (-C-C 8 ) -alkoxy, preferably methoxy and ethoxy, halogen, straight-chain or branched aryl- (C-C 8 ) -alkoxy, preferably benzyloxy or phenylethyloxy, Trityloxy,
  • (-C-C 8 ) alkoxy preferably benzyloxy or phenylethyloxy, trityloxy, trimethylsilyloxy, amino, mono- (C d) alkylamino, di- (C ⁇ -C 4 ) alkylamino, (C 2 - C 5 ) cycloalkylamino, morpholino , Heterocyclyl- (dC 6 ) -alkoxy, carboxy, imidocarboxy, carboxamidine, straight-chain or branched (dC 8 ) -alkoxycarbonylamino, straight-chain or branched (CrC 8 ) -alkylcarbonylamino, preferably
  • (Ci -C) alkyl-radical May be substituted (Ci -C) alkyl-radical, where the (Ci-C4) -alkyl radical can be unsubstituted or mono- or polysubstituted by identical or different (Ci-C6) alkyl or halogen, and the 2-, 6-, 7- or 8- [7H] -purinyl residue one to three times the same or different with hydrogen, straight-chain or branched (C r C 8 ) -alkyl, (C 3 -C 7 ) - cycloalky, straight-chain or branched (-C-C 8 ) alkylcarbonyl, preferably
  • Trimethylsilyloxy amino, mono- (CC) -alkylamino, di- (-C-C 4 ) -alkylamino, (C 2 - C 5 ) cycloalkylamino, morpholino, heterocyclyl- (dC 6 ) -alkoxy, carboxy, imidocarboxy, carboxamidine, straight-chain or branched (dC 8 ) -alkoxycarbonylamino, straight-chain or branched (-C-C 8 ) -alkylcarbonylamino, preferably acetamino, sulfonyloxy, sulfenyloxy, sulfinyloxo, nitro, nitroso, thio, straight-chain or branched (C ⁇ -C 8 ) -alkylthio, straight branched (dC 8 ) -alkylsulfo, straight-chain or branched (CC 8 ) -alkylsulf
  • the (Ci -C 6 ) alkyl radical may be unsubstituted or substituted one or more times identically or differently by hydrogen, (C 1 -C 6 ) -alkyl, or halogen and the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8 - or 9-phenanthridinyl residue unsubstituted or one to eight times the same or different with straight-chain or branched (C 1 -C 8 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, straight-chain or branched (CrC 8 ) -alkylcarbonyl, preferably Acetyl, hydroxy, straight-chain or branched (d
  • a 2-, 3-, 4-, 5, - or 6-pyridyl radical the 2-, 3-, 4-, 5, - or 6-pyridinyl radical being one to four times identical or different with hydrogen, straight-chain or branched (dC 8 ) alkyl, (C 3 -C 7 ) cycloalkyl, straight-chain or branched (Ci
  • C 8 ) -alkylcarbonyl preferably acetyl, hydroxy, straight-chain or branched (dd) -alkoxy, preferably methoxy and ethoxy, halogen, straight-chain or branched aryl- (CC 8 ) -alkoxy, preferably benzyloxy or phenylethyloxy, trityloxy, trimethylsilyloxy, amino, Mono- (CC 4 ) -alkylamino, di- (C 1 -C 4 ) -alkylamino, (C -C 5 ) cycloalkylamino, morpholino, heterocyclyl- (-C-C 6 ) -alkoxy, carboxy,
  • (Ci -C 6 ) alkyl or halogen can be substituted and the 2-, 3-, 4-, 5, - or 6-pyridinyl radical one to four times the same or different with hydrogen, straight-chain or branched (-C-C 8 ) -alkyl, (C 3 -C 7 ) -cycloalky, straight-chain or branched (-C-C 8 ) -alkylcarbonyl, preferably acetyl, hydroxy, straight-chain or branched (dC 8 ) -alkoxy, preferably methoxy and ethoxy, halogen, straight-chain or branched aryl (C 1 -C 8 ) alkoxy, preferably benzyloxy or phenylethyloxy, trityloxy, trimethylsilyloxy, amino, mono- (C 1 -C) alkylamino, di- (d-
  • C 8 ) -alkyl straight-chain or branched (-C-C 8 ) -alkoxycarbonyl- (-C-C 6 ) -alkyl, (C 2 - C 6 ) -alkenyl, preferably allyl, (C 2 -C 6 ) -alkynyl, preferably ethynyl or propargyl, may be substituted;
  • the (Ci -C 6 ) -alkyl radical may be unsubstituted or substituted one or more times, identically or differently, with (C 1 -C 6 ) -alkyl or halogen and the 2-, 3-, 4, - or 5-thienyl radical may be one to three times identical or different with hydrogen, straight-chain or branched (CC 8 ) alkyl, (C 3 -C 7 ) cycloalkyl, straight-chain or branched (-C-C 8 ) alkylcarbonyl, preferably acetyl, hydroxy, straight-chain or branched (dC 8 ) alkoxy , preferably methoxy and ethoxy, halogen, straight-chain or branched aryl- (dC 8 ) -alkoxy, preferably benzy
  • C 4 ) -alkyl preferably trifluoromethyl, straight-chain or branched carboxy- (CC 8 ) -alkyl, straight-chain or branched (C ⁇ -C 8 ) -alkoxycarbonyl- (dC 6 ) -alkyl, (C 2 - C 6 ) -alkenyl, preferably allyl, (C 6 -C 6 ) alkynyl, preferably ethynyl or propargyl, may be substituted;
  • a 2-, 4-, or 5-thiazolyl radical or 2-, 4-, or 5-thiazolyl- (-C -C 6 ) alkyl radical the (Ci -C 6 ) alkyl radical being unsubstituted or can be substituted one or more times identically or differently with (C 1 -C 6 ) -alkyl or halogen and the 2-, 4-, or 5-thiazolyl radical can be substituted once or twice identically or differently with hydrogen, straight-chain or branched (C ⁇ -C 8 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, straight-chain or branched (CC 8 ) -alkylcarbonyl, preferably acetyl, hydroxy, straight-chain or branched (CC 8 ) -alkoxy, preferably methoxy and ethoxy, halogen, straight-chain or branched aryl- (dC 8 ) -alkoxy, preferably benzyloxy or
  • C 6 ) alkenyl preferably allyl, (C 2 -C 6 ) alkynyl, preferably ethynyl or propargyl, may be substituted; a 3-, 4-, or 5-isothiazolyl radical or 3-, 4-, or 5-isothiazolyl- (d-C 6 ) -alkyl radical, the (C 1 -C 6 ) -alkyl radical being unsubstituted or one or more times the same or different can be substituted with (Ci-C 6 ) alkyl or halogen and the 3-, 4-, or 5-isothiazolyl radical, one or two times the same or different with hydrogen, straight-chain or branched (C ⁇ -C 8 ) -alkyl, (C 3 -C) -cycloalky, straight-chain or branched (C ⁇ -C 8 ) -alkylcarbonyl, preferably acetyl, hydroxy, straight-chain or branched (CC 8 )
  • C 8 ) -alkyl straight-chain or branched (-C-C 8 ) -alkoxycarbonyl- (-C-C 6 ) -alkyl, (C 2 - C 6 ) -alkenyl, preferably allyl, (C 2 -C 6 ) -alkynyl, preferably ethynyl or propargyl, may be substituted;
  • (C 1 -C 6 ) alkyl radical where the (C 1 -C 6 ) alkyl radical may be unsubstituted or substituted one or more times in the same or different ways with (d -C 6 ) alkyl or halogen and the 2- , 4-, 5-, 6-, or 7-benzothiazolyl radical one to four times the same or different with hydrogen, straight-chain or branched (C r C 8 ) alkyl, (C 3 -C 7 ) cycloalky, straight-chain or branched (-C-C 8 ) alkylcarbonyl, preferably
  • (Ci -C 6 ) alkyl radical where the (Ci -C 6 ) alkyl radical may be unsubstituted or substituted one or more times in the same or different ways with (Ci -C 6 ) alkyl or halogen and the 1- , 2-, 4-, or 5-imidazolyl radical one to three times the same or different with hydrogen, straight-chain or branched (-C-C 8 ) alkyl, (C 3 -C 7 ) - cycloalky, straight-chain or branched (C ⁇ -C 8 ) alkylcarbonyl, preferably acetyl, hydroxyl, straight-chain or branched (CC 8 ) alkoxy, preferably methoxy and ethoxy, halogen, straight-chain or branched aryl- (-C-C 8 ) alkoxy, preferably benzyloxy or phenylethyloxy, trityloxy, Trimethylsilyloxy, amino,
  • a 1-, 3-, 4- or 5-pyrazolyl radical or 1-, 3-, 4- or 5-pyrazolyl- (-C -C 6 ) alkyl radical the (d -C 6 ) alkyl -Rest unsubstituted or one or more times the same or may be differently substituted with (d -C 6 ) -alkyl or halogen and the 1-, 3-, 4- or 5-pyrazolyl radical may be mono- to triple the same or different with hydrogen, straight-chain or branched (CC 8 ) -alkyl , (C 3 -C 7 ) cycloalky, straight-chain or branched (-C-C 8 ) alkylcarbonyl, preferably acetyl, hydroxy, straight-chain or branched (C ⁇ -C 8 ) alkoxy, preferably methoxy and ethoxy, halogen, straight-chain or branched Aryl- (dC 8 ) -alkoxy, preferably benzyloxy or pheny
  • (Ci -C 6 ) alkyl radical where the (Ci -C 6 ) alkyl radical may be unsubstituted or substituted one or more times in the same or different ways with (Ci -C 6 ) alkyl or halogen and the 1- , 2, - 3, - 4, - or 5-pyrrolyl radical one to four times the same or different with hydrogen, straight-chain or branched (C r C 8 ) -alkyl, (C 3 -C 7 ) - cycloalky, straight-chain or branched (-C-C 8 ) -alkylcarbonyl, preferably acetyl, hydroxy, straight-chain or branched (CC 8 ) -alkoxy, preferably methoxy and ethoxy, halogen, straight-chain or branched aryl- (dC 8 ) -alkoxy, preferably benzyloxy or phenylethyloxy, trityloxy , Trimethyl
  • (CC 8 ) -alkylcarbonylamino preferably acetamino, sulfonyloxy, sulfenyloxy, sulfinyloxo, nitro, nitroso, thio, straight-chain or branched (-C-C 8 ) -alkylthio, straight-chain or branched (-C-C 8 ) -alkylsulfo, straight-chain or branched ( dC 8 ) alkylsulfoxy, cyano; , Isocyano, straight-chain or branched cyano- (C 1 -C 6 ) -alkyl, preferably cyanomethyl, straight-chain or branched (dC 8 ) -
  • a 1-, 4-, or 5- [1.2.3] thazolyl radical or 1-, 4-, or 5- [1.2.3] triazolyl- (-C -C 6 ) - alkyl radical the may be substituted (Ci -C 6) unsubstituted alkyl radical or mono- or polysubstituted by identical or different (Ci-C6) alkyl or halogen, and the 1-, 4-, or 5- [1.2.3] thazolyl radical or 1-, 4-, or 5- [1.2.3] triazolyl- (-C -C 6 ) - alkyl radical, the may be substituted (Ci -C 6) unsubstituted alkyl radical or mono- or polysubstituted by identical or different (Ci-C6) alkyl or halogen, and the 1-, 4-, or 5- [1.2.3] triazolyl- (-C -C 6 ) - alkyl radical, the may be substituted (Ci -C 6) unsubstituted al
  • (d -C 6 ) alkyl radical may be unsubstituted or substituted one or more times, identically or differently, with (C, -C 6 ) alkyl or halogen, and the 1- or 5- [1 Hj-tetrazolyl Radical with hydrogen, straight-chain or branched (dC 8 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, straight-chain or branched (-C-C 8 ) -alkylcarbonyl, preferably acetyl, hydroxy, straight-chain or branched (CC 8 ) - Alkoxy, preferably methoxy and ethoxy, halogen, straight-chain or branched aryl- (-C-C 8 ) -alkoxy, preferably benzyloxy or phenylethyloxy, trityloxy, trimethylsilyloxy, amino, mono- (-C-C 4 ) alkylamino,
  • a 2- or 5- [2H] tetrazolyl radical or 2- or 5- [2tf] tetrazolyl (C 1 -C 6 ) alkyl radical the (C 1 -C 6 ) alkyl radical being unsubstituted or may be substituted one or more times, identically or differently, with (C 1 -C 6 ) -alkyl or halogen and the 2- or 5- [2H] -tetrazolyl radical may be substituted with hydrogen, straight-chain or branched (-CC 8 ) -alkyl, (C 3 -C 7 ) cycloalky, straight-chain or branched (-C-C 8 ) alkylcarbonyl, preferably acetyl, hydroxy, straight-chain or branched (dC 8 ) alkoxy, preferably methoxy and ethoxy, halogen, straight-chain or branched aryl- ( C 1 -C 8 -alkoxy, preferably benzy
  • Carboxamidine linear or branched (C ⁇ -C8) alkoxycarbonylamino, straight or branched (C ⁇ -C8) alkylcarbonylamino, preferably acetamido, sulfonyloxy, Sulfenyloxy, Sulfinyloxo, nitro, nitroso, thio, straight or branched (dC 8) alkylthio , straight-chain or branched (dC 8 ) - alkylsulfo, straight-chain or branched (C ⁇ -C 8 ) -alkylsulfoxy, cyano, isocyano, straight-chain or branched cyano ⁇ d-dValkyl, preferably cyanomethyl, straight-chain or branched (C ⁇ -C 8 ) -alkoxycarbonyl , with one or more halogen atoms substituted, straight-chain or branched (CC) -alkyl, preferably trifluoromethyl, straight
  • Alkenyl preferably allyl, (C 2 -C 6 ) alkynyl, preferably ethynyl or propargyl, may be substituted;
  • the (Ci-C 6 ) -alkyl radical may be unsubstituted or substituted one or more times, identically or differently, with hydrogen, (d-C 6 ) -alkyl or halogen and the 2-, 4- or 6- [1.3.5 ] -Triazinyl radical, one or two times the same or different, with hydrogen, straight-chain or branched (C 1 -C 8 ) -alkyl, (C 3 -C 7 ) - cycloalky, straight-chain or branched (dC 8 ) -alkylcarbonyl, preferably acetyl, Hydroxy, straight chain or branched (CC 8 ) alkoxy, preferably
  • a 2-, 4-, or 5-oxazolyl radical or 2-, 4-, or 5-oxazolyl- (-C -C 6 ) alkyl radical the (Ci -C 6 ) alkyl radical being unsubstituted or may be substituted one or more times, identically or differently, with (C 1 -C 6 ) -alkyl or halogen and the 2-, 4-, or 5-oxazolyl radical may be, once or twice, the same or differently with hydrogen, straight-chain or branched (CC 8 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, straight-chain or branched (dC 8 ) -alkylcarbonyl, preferably acetyl, hydroxy, straight-chain or branched (dC 8 ) -alkoxy, preferably methoxy and ethoxy, halogen, straight-chain or branched Aryl- (dC 8 ) alkoxy, preferably benzyloxy or
  • C 6 ) alkenyl preferably allyl, (C 2 -C 6 ) alkynyl, preferably ethynyl or propargyl, may be substituted; a 3-, 4-, or 5-isoxazolyl radical or 3-, 4-, or 5-isoxazolyl- (-C -C 6 ) alkyl radical, the (Ci -C 6 ) alkyl radical being unsubstituted or can be substituted one or more times the same or different with (Ci-C 6 ) alkyl or halogen and the 3-, 4-, or 5-isoxazolyl radical can be substituted one or two times the same or different with hydrogen, straight-chain or branched (C ⁇ -C 8 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, straight-chain or branched (CrC 8 ) -alkylcarbonyl, preferably acetyl, hydroxy, straight-chain or branched (-
  • C 8 alkyl, straight-chain or branched (-C-C 8 ) alkoxycarbonyl- (dC 6 ) alkyl, (C 2 - C 6 ) alkenyl, preferably allyl, (C 2 -C 6 ) alkynyl, preferably ethynyl or propargyl, may be substituted;
  • (Ci -C 6 ) alkyl radical where the (Ci -C 6 ) alkyl radical may be unsubstituted or substituted one or more times in the same or different ways with (Ci -C 6 ) alkyl or halogen and the 1- , 2-, 3-, 4-, 5-, 6- or 7-indolyl radicals one to six times the same or different with hydrogen, straight-chain or branched (-CC 8 ) -alkyl, (C 3 -C 7 ) - Cycloalky, straight-chain or branched (dC 8 ) -alkylcarbonyl, preferably
  • anthracene derivatives according to the general formula 1 are provided, characterized in that R, R 1 ( R 2 , R 3 , Z, n and m have the meanings given above and R 4 is phenyl which is unsubstituted or is substituted with one to five identical or different (CrC 6 ) alkoxy groups, adjacent oxygen atoms also being able to be linked by (C 1 -C 2 ) alkylene groups.
  • anthracene derivatives according to the general formula 1 are provided, characterized in that R, R 1, R 2 , R, Z, n and m have the meanings given above and R 4 is 3,5-dimethoxyphenyl.
  • anthracene derivatives according to general formula 1 are provided, characterized in that R and Z have the meaning given above, R, Ri, R 2 ⁇ .R 3 each represent a hydrogen atom, m is 1 and n stands for the integer 1 and 2.
  • anthracene derivatives according to general formula 1 are provided, characterized in that R, Ri, R 2 and R 3 each represent a hydrogen atom, Z has the meaning given, m and n represent the integer 1 and R 4 represents a 3,5-dimethoxyphenyl radical.
  • anthracene carboxylic acid of the general formula 2 wherein R, R 1 ( R 2 , R 3 the above have the meanings mentioned, Z represents an oxygen or sulfur atom and Y represents a leaving group such as halogen, hydroxy, (dC 6 ) - alkoxy, preferably methoxy and ethoxy, -O-tosyl, -O-mesyl, tetrazolyl or imidazolyl,
  • the starting compounds 2 and 3 are either commercially available or can be prepared by processes known per se.
  • the starting materials 2 and 3 are valuable intermediates for the preparation of the anthracene derivatives of the formula 1 according to the invention.
  • reaction parameters to be used such as reaction temperature and duration, are known to the person skilled in the art on the basis of his expert knowledge.
  • the anthracene derivatives according to the invention according to general formula 1 are suitable as active ingredients in medicaments, in particular as antitumor agents, for the treatment of humans and mammals.
  • Mammals can be pets such as horses, cows, dogs, cats, rabbits, sheep, poultry and the like.
  • the medicinal effect of the anthracene derivatives according to the invention can be based, for example, on an interaction with the tubulin system by inhibiting tubulin polymerization.
  • other known and unknown mechanisms of action to combat tumor cells are also conceivable.
  • a method for combating tumors in humans and in mammals which is characterized in that at least one anthracene derivative according to general formula 1 is administered to humans or a mammal in an amount effective for the treatment of tumors becomes.
  • the therapeutically effective dose of the respective anthracene derivative according to the invention to be administered for the treatment depends, inter alia, on the type and stage of the tumor disease, the age and gender of the patient, the type the administration and duration of treatment.
  • the pharmaceuticals according to the invention can be administered as liquid, semi-solid and solid pharmaceutical forms.
  • the pharmaceutical forms optionally contain auxiliaries, such as, inter alia, solvents, solution accelerators, solubilizers, emulsifiers, wetting agents, anti-foaming agents, gel formers, thickeners, film formers, binders, buffers, salt formers, drying agents, flow regulators, fillers, preservatives , Antioxidants, dyes, mold release agents, lubricants, disintegrants, taste and smell correctives.
  • auxiliaries such as, inter alia, solvents, solution accelerators, solubilizers, emulsifiers, wetting agents, anti-foaming agents, gel formers, thickeners, film formers, binders, buffers, salt formers, drying agents, flow regulators, fillers, preservatives , Antioxidants, dyes, mold release agents, lubricants, disintegrants, taste and smell correctives.
  • auxiliaries such as, inter alia, solvents, solution accelerators, solubilizers, emulsifiers
  • the medicaments according to the invention can be applied to the skin in a suitable dosage form, epicutaneously as a solution, suspension, emulsion, foam, ointment, paste or plaster; via the oral and tongue mucosa, buccal, lingual or sublingual as a tablet, lozenge, dragees, linctus or gargle water; via the gastric and intestinal mucosa, enterally as tablets, coated tablets, capsules, solutions, suspensions or emulsions; via the rectal mucosa, rectally as a suppository, rectal capsule or ointment; through the nasal mucosa, nasally as drops, ointments or spray; via the bronchial and alveolar epithelium, pulmonary or by inhalation as aerosol or inhalation; via the conjunctiva, conjunctival as eye drops, eye ointment, eye tablets, lamellae or eyewash; via the mucous membranes of the genital organs,
  • Drug effect can be extended. This goal can be achieved chemically and / or galenically. Examples of how to achieve an extension of effectiveness are the use of implants and liposomes, the formation of poorly soluble salts and complexes or the use of crystal suspensions.
  • Drugs which contain at least one compound from the following group of aryl derivatives are particularly preferred:
  • Anthracen-9-yl- [4- (4-nitro-phenyl) piperazin-1-yl] methanone (1) Anthracen-9-yl- [4- (3,5-dimethoxy-phenyl) piperazin-1 -yl] -methanone (2) anthracen-9-yl- [4-phenyl) -piperazin-1-yl] -methanone (3) anthracen-9-yl- (4-naphthalen-1-yl-piperazin-1- yl) -methanone (4) anthracen-9-yl- (4-biphenyl-2-yl-piperazin-1-yl) -methanone (5) anthracen-9-yl- [4- (3-hydroxy-phenyl) - piperazin-1-yl] -methanone (6) anthracen-9-yl- [4- (4-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] -me
  • Table 1 New anthracene derivatives with anti-tumor effects
  • the most preferred compounds of the present invention are substances of general formula 1 in the form of their bases or their pharmaceutically acceptable salts, which are selected from the following group:
  • the substance according to Example 2 was examined for its anti-proliferative activity in a proliferation test on established tumor cell lines.
  • the test used determines the cellular dehydrogenase activity and enables a determination of the cell vitality and indirectly the cell number.
  • the cell lines used are the human cervical carcinoma cell line KB / HeLa (ATCC CCL17), the ovarian adenocarcinoma cell line SKOV-3 (ATCC HTB77), the human glioblastoma cell line SF-268 (NCI 503138) and the lung carcinoma cell line NCI H460 (NCI 503473).
  • an RKOp27 cell system was used to investigate the cell cycle-specific effect of the substance (M.Schmidt et al.
  • RKO is a human colon carcinoma line in which the cell cycle inhibitor p27 klp1 can be induced to be induced by means of the Ecdyson expression system and can be brought about in a cell cycle arrest specifically in G2.
  • An unspecific substance inhibits the Proliferation regardless of whether the RKO cell is locked in G1 or G2 or not.
  • cell cycle-specific substances such as tubulin inhibitors are only cytotoxic if cells are not locked and the cell cycle is followed.
  • Table 2 shows the cytotoxic or growth-inhibiting activity of the described compound with / without expression of p27 kip1 .
  • the tested compound showed no cytotoxic activity in the induced state of p27 k ⁇ p1 .
  • the results show a very potent inhibition of the proliferation of selected tumor cell lines by the substance named as example 2.
  • substance 2 was examined for its anti-proliferative effect on a panel of 12 human tumor cell lines.
  • the cell lines examined are the human glioma cell lines A172 (ATCC CRL-1620), U1 18 (ATCC HTB-15) and U373 (ATCC HTB-17), the rat glioma cell line C6 (ATCC CCL-107) human lung carcinoma cell line A549, human epidermoid carcinoma A431 (ATCC CRL-2592), human prostate carcinoma cell lines DU 145 (ATCC HTB-81) and PC3 (ATCC CRL-1435), human colon adenocarcinoma cell line HT29 (ATCC HTB-38), the human pancreas adenocarcinoma cell line ASPC1 (ATCC CRL-1682) as well as the human breast carcinoma cell lines T47D (ECACC 88062428) and MDAMB435 (NCI 914182).
  • Table 3 Inhibitory effect of substance 2 in the XTT proliferation test on human tumor cell lines. The average values from two independent tests are given.
  • Substance 2 was tested in an in vitro test for inhibition of the polymerization of bovine tubulin.
  • tubulin purified by cycles of polymerization and depolymerization is used, which is brought to polymerization by adding GTP and heating.
  • Table 4 shows the EC 50 values of the inhibition of polymerization of tubulin with 30% associated proteins (MAPs) and of MAP-free tubulin. The results show a very potent inhibitory effect of substance 2 on the polymerization of tubulin.
  • Table 4 Inhibition of tubulin polymerization. Average of two independent tests.
  • the adherent growing tumor cell lines KB / HeLa, SKOV-3, SF-268, NCI-H460, ASPC1, A172, A431, A549, DU145, C6, MDAMB435, HT29, PC3, T47D, U118MG and U373MG were cultivated under standard conditions in the gassing incubator at 37 ° C, 5% CO 2 and 95% humidity.
  • the cells are detached with trypsin / EDTA and pelleted by centrifugation.
  • the cell pellet is then resuspended in the respective culture medium in the appropriate cell number and converted into a 96-well microtiter plate.
  • the plates are then cultivated overnight in the fumigation incubator.
  • test substances are prepared as 1 mg / ml stock solutions in DMSO and diluted with culture medium in the appropriate concentrations on test day 2. The substances in culture medium are then added to the cells and incubated for 45 hours in the fumigation incubator. Cells that are not treated with test substance serve as a control.
  • XTT sodium 3 '- [1- (phenylaminocarbonyl) -3,4-tetrazolium] bis (4-methoxy-6-nitro) benzenesulfonic acid
  • RPMI-1640 medium without phenol red
  • PMS N-methyl dibenzopyrazine methyl sulfate
  • PBS phosphate-buffered saline
  • the XTT solution is mixed with the PMS solution in a ratio of 50: 1 (vol: vol) shortly before use.
  • the cell plates are then incubated in the gassing incubator for a further 3 hours and the optical density (OD 90 ⁇ m ) is determined in the photometer.
  • the optical density OD 90 ⁇ m
  • the percent inhibition relative to the control and a concentration response curve plotted semi-logarithmically in shape.
  • the EC 50 is calculated using a regression analysis from the concentration-effect curve using the Graphpad Prism program.
  • the assay is carried out in 96-well plates. By inducible expression of p27 k ⁇ p1 , the cells are completely arrested for growth, but do not die. By comparing the effectiveness on induced and non-induced cells, conclusions can be drawn about the mechanism of action (cell cycle specificity) of the therapeutic agents. Uninduced cells are sown in approximately three times the number of cells, since there is no division during the assay compared to uninduced cells (20,000 cells / well induced, 6,250 cells / well not induced). The controls are untreated cells (+/- induction). Induction is carried out with 3 ⁇ M Muristeron A. On the 1st day the cells are exposed (+/- Muristeron A) and incubated for 24 hours at 37 ° C. On day 2, the test substance is added (control DMSO) and incubated for a further 45 h at 37 ° C. before a standard XTT assay is carried out. Tubulin polymerization assay
  • Lyophylized bovine tubulin (cytoskeleton, ML113 tubulin 30% MAPs, TL238 tubulin MAP free) is used in a concentration of 2mg / ml (ML113 in 80mM PIPES, 0.5mM EGTA, 2mM MgCl 2 , pH6.9, 1mM GTP). or 5mg / ml (TL238m 80mM PIPES, 1mM EGTA, 0.5mM MgCl 2 , 20% (v: v) glycerol pH6.9, 1mM GTP) dissolved.
  • test substances are diluted in 10% DMSO (v: v) and 5 ⁇ l of the dilutions are transferred to a 96-well microtiter plate (Nunc, half area plate).
  • a 96-well microtiter plate (Nunc, half area plate).
  • the polymerization at 340nm is determined in a Spectramax 190 microtiter plate reader (molecular devices) using a kinetics program at 30sec intervals over a period of 20min.
  • the resulting area under curve values are used to calculate the inhibition in relation to the untreated control and are plotted in the form of a concentration-activity curve using half log.
  • the EC 50 is calculated using a regression analysis from the concentration-effect curve using the Graphpad Prism program. induced).
  • the controls are untreated cells (+/- induction). Induction is carried out with 3 ⁇ M Muristeron A. On the 1st day the cells are exposed (+/- Muristeron A) and incubated for 24 hours at 37 ° C. On day 2, the test substance is added (control DMSO) and incubated for a further 45 h at 37 ° C. before a standard XTT assay is carried out.
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing. This powder mixture is filled into size 3 hard gelatin capsules on a capsule filling machine.

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Abstract

L'invention concerne de nouveaux dérivés d'anthracène correspondant à la formule générale (I), leur production et leur utilisation comme médicaments, en particulier pour le traitement de tumeurs.
EP03763626A 2002-07-17 2003-05-16 Nouveaux derives d'anthracene et leur utilisation comme medicaments Withdrawn EP1521748A1 (fr)

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FR2871157A1 (fr) * 2004-06-04 2005-12-09 Aventis Pharma Sa Produits biaryl aromatiques, compositions les contenant et utilisation
EP1645556A1 (fr) * 2004-10-07 2006-04-12 Boehringer Ingelheim International GmbH Derives d'arylpiperazine-benzoylamide utiles comme agents pharmaceutiques
JP2009508150A (ja) 2005-09-13 2009-02-26 カール・ツァイス・エスエムティー・アーゲー マイクロリソグラフィ投影光学系、ある機器を製造するための方法、光学面を設計する方法
WO2008015265A1 (fr) * 2006-08-04 2008-02-07 Æterna Zentaris Gmbh Dérivés de l'anthracène et leur utilisation pour le traitement d'affections tumorales bénignes et malignes
EP1897864A1 (fr) * 2006-08-07 2008-03-12 AEterna Zentaris GmbH Derivés anthracènes et l'utilisation en traitement de cancer
EA030302B1 (ru) * 2008-11-21 2018-07-31 Форест Лэборетериз Холдингз Лимитед Антрахинондиоксимы и их применение
CN105837478B (zh) * 2016-04-20 2017-11-14 成都理工大学 作为p2x3和p2x2/3受体拮抗剂的双磺酰基蒽二酮双肟衍生物

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US5110927A (en) * 1987-12-31 1992-05-05 The United States Of America As Represented By The Department Of Health And Human Services Prazosin analog with increased selectivity and duration of action
DE10035928A1 (de) * 2000-07-21 2002-03-07 Asta Medica Ag Neue Heteroaryl-Derivate und deren Verwendung als Arzneimittel
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MXPA05000487A (es) 2005-03-23
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US20040110756A1 (en) 2004-06-10

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